For a number of years, the scientific and medical communities have been continually exploring the possibility of using radionuclides for cancer therapy. The use of sealed radioactive sources e.g., radium needles and capsules is now commonplace. However, with the exception of a select number of applications, the hopes of employing unsealed sources for the radiotherapy of a neoplastic disease remain largely unrealized. The problem has two components: (a) a scarcity of appropriate radionuclides, and (b) developing appropriate carrier molecules that can (i) bring the radionuclide into the vicinity of cancerous cells and (ii) incorporating the radionuclide into the tumor cells so as to achieve high ratios of the radionuclide between tumor cells and normal tissues.
The biological toxicity of internally deposited radionuclides can be attributed to radiation-induced ionizations and excitations, nuclear recoil, chemical transmutations, and local charge effects. Gamma and x-ray photons, energetic negatrons and positions have (i) a range of action equivalent to many cell diameters, (ii) are characterized by a low linear energy transfer LET and oxygen-dependent biological effects. On the other hand, radionuclides that decay by electron capture (EC) and/or internal conversion (IC) demonstrate an Auger effect in which extremely low energy, i.e.&lt;1 KeV, short range electrons are produced which dissipate their energy typically within nanometer distances from the decay site. Consequently, the biological toxicity of these radionuclides resembles that of high LET radiations and is critically dependent on their intranuclear localization. Furthermore, the oxygen enhancement ratios (OER) obtained following their decay are smaller than those seen with x-irradiation and energetic particles.
The Auger-electron-emitting radionuclide investigated most extensively is iodine-125. Because of its predominant IC decay following EC (approximately 93%), this radionuclide is a prolific emitter of Auger electrons. The electrons most frequently produced dissipate their energy in the immediate vicinity of the decaying atom and deposit 10.sup.5 -10.sup.9 rad/decay within 20-to-60-nanometer spheres around the decaying atom. The radiotoxicity of this Auger electron emitter was demonstrated following the in vitro incorporation of the thymidine [TdR]analog .sup.125 IUdR into the DNA of dividing mammalian cells. Further in vitro studies indicate that these and other Auger electron emitters have shown a decrease in radiotoxicity when emission occurs at a distance from the nuclear DNA.
5-Iodo-2'-deoxyuridine (IUdR) is a thymidine analog in which the 5-methyl group of thymidine (TdR) is replaced by iodine. IUdR specifically incorporates into DNA during the synthetic phase of the cell cycle. Most DNA incorporated IUdR is retained for the life of the cell or its progeny. In contrast, the unincorporated IUdR is rapidly catabolized to iodouracil and/or dehalogenated while its half-life in circulation is very short, i.e. less than five minutes in humans and less than seven minutes in a mouse. The preparation of this compound as well as the iodinated .sup.123 I and .sup.125 I versions are fully described in U.S. Pat. No. 4,851,520 the teachings of which are incorporated herein by reference.
Briefly, 2'-deoxyuridine (0.50 g, 2.20 mmol) is dissolved in 2 ml water and the solution is heated to 50.degree. C. To this solution, mercuric acetate (0.74 g, 2.32 mmol) in 3 ml of water is added. The reaction is allowed to proceed for 2.5 h at 50.degree. C., the vial cooled down to 40.degree. C., and sodium chloride (0.32 mg, 5.45 mmol) in 1 ml of water is added. The reaction mixture is stirred for 1 h, and the suspension is filtered, washed and dried.
To 6 mg (8.6 .mu.mol) of the thus prepared 5-chloro-2'-deoxyuridine, 4 mg of Iodogen (9.3 .mu.mol) and sodium .sup.123 I/.sup.125 I]iodide [1-10 mCi) in 0.3 ml of water are added. The mixture is stirred in a closed 2-ml reaction vial at room temperature for 2 h, filtered through a 0.22 .mu.m Millex filter, and injected into the HPLC (C.sub.18 column). Fractions from the peak with a retention time (R.sub.T) of 7.1 min (corresponding to that of an authentic cold IUdR sample) are pooled, the eluant (H.sub.2 O/CH.sub.3 OH,80/20 by volume) evaporated, and the .sup.123 IUdR or .sup.125 IUdR resuspended in saline and sterilized e.g., by filtration, prior to administration into the mammals.
Despite the fact that various pharmaceuticals that exhibit high in vitro toxicity to mammalian cells have been identified over the years, none of these have demonstrated any "magic bullet" characteristics in vivo. To facilitate targeting of tumors, investigators have relied on the direct introduction of the therapeutic/diagnostic agents either into the target area or into an arterial blood supply that immediately precedes the target. Inherent to the absolute success of such approaches are four main assumptions:
1. the target is approximately within an area that can be easily accessed;
2. once within the vicinity of the tumor-containing tissues, the agent (a) freely diffuses throughout all the tissues, (b) is innocuous outside the cell, and (c) is selectively taken up either passively or actively and indefinitely retained by each and every cancerous cell but not by noncancerous cells;
3. once the agent has diffused out of the target area, it must either be converted quickly into an inactive, i.e., nontoxic, form and/or be excreted from the body;
4. the biologic behavior of the agent is not altered by repeated injection, i.e., it lends itself to repeat/continuous injections.